This invention relates to a cost effective process for producing chiral intermediates useful in the synthesis of 1-(dethia)carbacephem antibiotics. More particularly, this invention is directed to the synthesis of chiral epoxybutyrates via novel dihydro-3R,4R-dihydroxy-2(3H)furanone 3-sulfonic acid esters.
The ability to introduce a chiral center is critical to the synthesis of many commercially significant biologically active compounds. When only one enantionmer is active, yield losses result not only from production of the inactive stereoisomer but also during separation and recovery of the desired product. In synthetic procedures involving multiple steps, low yielding steps, especially those early in the synthetic route, seriously affect the economics of the synthesis. Thus, there has been a continuing effort toward the development of chemistry relying on asymmetric induction to provide products of preferred stereochemical configuration. One particular area of such effort has been the stereoselective synthesis of .beta.-lactam intermediates useful for the production of mono-bactams, clavulanic acid, thienamycin, and the 1-carba(1-dethia)cephalosporins. Among the more efficient methods for stereospecific construction of the .beta.-lactam ring is the so-called ketene-imine cycloaddition comprising the reaction of an amino-protected glycyl chloride or other ketene generating derivative with an imine in the presence of a tertiary amine. For example, Evans et al., in U.S. Pat. No. 4,665,171 describe an asymmetric method for preparing the .beta.-lactam ring which comprises a cyclo addition of an imine with a chiral 4-(S)-aryloxazolidin-2-on-3-yl-acetyl halide wherein the chiral aryl oxazolidinone functions to induce the desired chirality in the product azetidinones. A related method for synthesizing optically active .beta.-lactams starting from optically active alpha-amino acids is described and claimed by Sugawara et al. in published European Application No. 144,840. Still another chiral synthesis of .beta.-lactam intermediates is described in co-pending U.S. application Ser. No. 07/173,381, now allowed. That application describes a method for preparing .beta.-lactam intermediates wherein the chirality of the .beta.-lactam ring is induced with a chiral epoxy aldehyde employed to form the imine for use in a ketene-imine cycloaddition.
While each of those chiral syntheses offer the advantage of enhanced stereoselectivity, such advantages are offset by the expense of preparing the chirality inducing optically active intermediates. Thus, for example, the chiral epoxy aldehydes used to form the imine intermediates for cyclo addition with ketenes in accordance with the disclosure of Evans in the above referenced U.S. application Ser. No. 07/173,381 are, from a commercial perspective, not economically viable intermediates. Ongoing research and development efforts have been directed toward methods of synthesis of important chiral auxiliaries for the stereo selective production of .beta.-lactam containing intermediates.
This invention provides a cost efficient synthesis of chiral 4-hydroxy-2,3-epoxybutyrate esters from novel, but readily available, chiral dihydro-3,4-dihydroxy-2(3H)furanone 2-sulfonic acid esters. The sulfonic acid ester intermediates are prepared in high yield from the corresponding dihydroxy furanones derived by peroxide oxidation of low cost isoascorbic acid or its sodium salt, sodium erythrobate. The chiral epoxybutyrate esters are oxidized in high yield using, for example, Swern oxidation conditions (oxalyl chloride, DMSO-triethylamine) to the corresponding chiral epoxy aldehydes which are key intermediates for the stereo selective synthesis of .beta.-lactams in accordance with the above described method of Evans. The present method utilizing novel dihydro-3,4-dihydroxy-2(3H)furanone 3-sulfonic acid esters provides a cost effective method for preparing the important epoxy aldehyde .beta.-lactam intermediates.